The aim of the proposed research is to carry out a systematic study of delayed hypersensitivity (DH) to Herpes simplex virus (HSV) to determine the role of this cell-mediated immune (CMI) response in protection against HSV infection and establishment of latency. Our approach is to use a model system we have developed in mice where animals are infected or immunized with wild-type or temperature-sensitive mutant HSV. Delayed hypersensitivity is assessed by challenging the mice with virus in the ears and measuring increased ear swelling with an engineer's micrometer. Use of mutant virus allows for control of virus replication in the host so various parameters of the CMI response can be investigated without the complication of actively growing virus. Furthermore, the mouse provides a system where different T cell subsets can be identified, characterized and easily manipulated. We propose to characterize the DH response with respect to the kinetics of induction and duration, the cell type(s) involved, their specificity and genetic requirements for activation. Using passive transfer of purified immune T cells to normal recipients, we will investigate the protective effect of established DH on primary HSV infection and establishment of latency. In addition, using established isolation procedures for glycoproteins together with HSV-1 x HSV-2 intertypic recombinants, we will investigate which of the cell surface viral glycoproteins is(are) recognized by the effector T cells. Finally, in a limited way, we will explore aspects of tolerance to HSV. Our purpose is to determine if, during the course of infection, the virus induces suppressor cells which limit the immune response and thus allow establishment of chronic or latent infection. Little is known concerning the DH response to HSV and its role in protection. We expect our studies to provide useful information which may be used in the development of improved treatment protocols utilizing immunopotentiators and/or active immunization.